Method of Initiating and Escalating Sotalol Hydrochloride Dosing

ABSTRACT

This disclosure provides a method of safely and rapidly initiating or escalating oral sotalol therapy by administering an intravenous dosage of sotalol followed by oral sotalol twice daily.

FIELD

This disclosure provides methods of treating or preventing atrialfibrillation, atrial flutter, or a combination thereof comprisingintravenously administering sotalol hydrochloride to subject in needthereof.

BACKGROUND

Sotalol hydrochloride (“sotalol”) is Vaughan Williams Class IIIanti-arrhythmic drug that prolongs cardiac action potential duration byblocking the outward potassium channel IKr (rapid potassium rectifiercurrent), thereby prolonging repolarization time.

Although sotalol is effective at treating or preventing atrialfibrillation, atrial flutter, and combinations thereof, sotalol'smechanism of action is both anti-arrhythmic and pro-arrhythmic. Too muchsotalol too fast can lead to excessive prolongation of repolarizationtime giving rise to life threatening arrhythmias, especially Torsade dePointes ventricular tachycardia (Tdp). Thus, it is well understood inthe art, that during sotalol's initial loading, or in a dose escalationintervention, it is critical to monitor a subject's QTc interval toavoid excessive QTc prolongation.

Due to sotalol's potential to induce arrhythmia, the FDA has mandatedin-hospital QTc monitoring for at least three days upon initial sotalolhydrochloride loading and for dose escalation. Although this extendedhospital stay is effective at reducing subject risk, maintaining thesubject in a telemetry unit for three days is extremely expensive,making sotalol a less desirable treatment choice in a managed careenvironment. A need therefore exists to develop methods of reducing thelength of hospital stay required to safely and efficaciously administersotalol to subjects in need thereof.

BRIEF SUMMARY

The present disclosure provides methods of safely intravenouslyadministering sotalol hydrochloride to subjects in need thereof over asignificantly reduced period of time, such as about 1 hour. Inparticular, the present disclosure provides a method of achieving asotalol steady state C_(max) after about 1 hour of intravenousadministration equal to the sotalol steady state C_(max) typicallyachieved after BID PO sotalol administration for three days.

In one embodiment, this disclosure provides a method of treating orpreventing atrial fibrillation, atrial flutter, or a combination thereofin a subject in need thereof, the method comprising intravenouslyadministering to the subject between about 0.825 mg/min and about 1.17mg/min of sotalol hydrochloride over a period of about 60 minutes.

In some embodiments, the method further comprises discontinuing orreducing intravenous administration of sotalol hydrochloride when thesubject has a QTc interval after intravenous sotalol hydrochlorideinitiation that is greater than 500 msec; or wherein the subject has aΔQTc that is greater than or equal to 20% of the subject's QTc prior tosotalol administration.

In some embodiments, the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about750 ng/mL and about 850 ng/mL in the subject.

In some embodiments, the method further comprises orally administeringto the subject 80 mg of sotalol hydrochloride between about 1 hour andabout 6 hours after completion of the intravenous administration.

In some embodiments, the method further comprises discontinuing orreducing oral administration of sotalol hydrochloride when the subjecthas a QTc interval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

In some embodiments, the method further comprises initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and about 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to intravenous sotalol administration.

Also provided is a method of treating or preventing atrial fibrillation,atrial flutter, or a combination thereof in a subject in need thereof,the method comprising intravenously administering to the subject betweenabout 1.23 mg/min and about 1.76 mg/min of sotalol hydrochloride over aperiod of about 60 minutes.

In some embodiments, the method further comprises discontinuing orreducing intravenous administration of sotalol hydrochloride when thesubject has a QTc interval after intravenous sotalol hydrochlorideinitiation that is greater than 500 msec; or wherein the subject has aΔQTc that is greater than or equal to 20% of the subject's QTc prior tosotalol administration.

In some embodiments, the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about1150 ng/mL and about 1250 ng/mL in the subject.

In some embodiments, the method further comprises orally administeringto the subject 120 mg of sotalol hydrochloride between about 1 hour andabout 6 hours after completion of the intravenous administration.

In some embodiments, the method further comprises discontinuing orreducing oral administration of sotalol hydrochloride when the subjecthas a QTc interval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

In some embodiments, the method further comprises initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and about 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to intravenous sotalol administration.

Also provided is a method of treating atrial fibrillation, atrialflutter, or a combination thereof in a subject in need thereof, themethod comprising intravenously administering to the subject betweenabout 1.65 mg/min to about 2.35 mg/min of sotalol hydrochloride over aperiod of about 60 minutes.

In some embodiments, the method further comprises discontinuing orreducing intravenous administration of sotalol hydrochloride when thesubject has a QTc interval after intravenous sotalol hydrochlorideinitiation that is greater than 500 msec; or wherein the subject has aΔQTc that is greater than or equal to 20% of the subject's QTc prior tosotalol administration.

In some embodiments, the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about1550 ng/mL and about 1650 ng/mL in the subject.

In some embodiments, the method further comprises orally administeringto the subject 160 mg of sotalol hydrochloride between about 1 hour andabout 6 hours after completion of the intravenous administration.

In some embodiments, the method further comprises discontinuing orreducing oral administration of sotalol hydrochloride when the subjecthas a QTc interval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

In some embodiments, the method further comprises initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% thesubject's QTc prior to intravenous sotalol administration.

Also provided is a method of treating or preventing atrial fibrillation,atrial flutter, or a combination thereof in a subject in need thereof,the method comprising intravenously administering to the subject betweenabout 0.825 mg/min and about 1.17 mg/min of sotalol hydrochloride over aperiod of about 60 minutes, wherein the subject received anadministration of sotalol hydrochloride between about 12 hours and about24 hours before the intravenous administration.

In some embodiments, the subject received an oral administration of 80mg of oral sotalol hydrochloride between about 12 and about 24 hoursbefore the intravenous administration.

In some embodiments, the method further comprises discontinuing orreducing intravenous administration of sotalol hydrochloride when thesubject has a QTc interval after intravenous sotalol hydrochlorideinitiation that is greater than 500 msec; or wherein the subject has aΔQTc that is greater than or equal to 20% of the subject's QTc prior tosotalol administration.

In some embodiments, the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about1150 ng/mL and about 1250 ng/mL in the subject.

In some embodiments, the method further comprises orally administeringto the subject 120 mg of sotalol hydrochloride between about 1 hour andabout 6 hours after completion of the intravenous administration.

In some embodiments, the method further comprises discontinuing orreducing oral administration of sotalol hydrochloride when the subjecthas a QTc interval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

In some embodiments, the method further comprises initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% thesubject's QTc prior to intravenous sotalol administration.

Also provided is a method of treating or preventing atrial fibrillation,atrial flutter, or a combination thereof in a subject in need thereof,the method comprising intravenously administering to the subject betweenabout 1.05 mg/min and 1.47 mg/min of sotalol hydrochloride over a periodof about 60 minutes, wherein the subject received an administration ofsotalol hydrochloride between about 12 hours and about 24 hours beforethe intravenous administration.

In some embodiments, the subject received an oral administration of 120mg of oral sotalol hydrochloride between about 12 and about 24 hoursbefore the intravenous administration.

In some embodiments, the method further comprises discontinuing orreducing intravenous administration of sotalol hydrochloride when thesubject has a QTc interval after intravenous sotalol hydrochlorideinitiation that is greater than 500 msec; or wherein the subject has aΔQTc that is greater than or equal to 20% of the subject's QTc prior tosotalol administration.

In some embodiments, the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about1550 ng/mL and about 1650 ng/mL in the subject.

In some embodiments, the method further comprises orally administeringto the subject 160 mg of sotalol hydrochloride between about 1 hour andabout 6 hours after completion of the intravenous administration.

In some embodiments, the method further comprises discontinuing orreducing oral administration of sotalol hydrochloride when the subjecthas a QTc interval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

In some embodiments, the method further comprises initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% thesubject's QTc prior to intravenous sotalol administration.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned features and objects of this disclosure will becomemore apparent with reference to the following description taken inconjunction with the accompanying drawings.

FIG. 1 is a line graph depicting initiation of an intravenous dose of 55mg of sotalol hydrochloride to achieve an estimated steady state C_(max)equivalent to the steady state C_(max) achieved via chronic oral twicedaily dosing of 80 mg sotalol hydrochloride in a subject with normalrenal function.

FIG. 2 is a line graph depicting dose escalation from 80 mg twice a dayto 120 mg twice a day of oral sotalol hydrochloride via the intravenousadministration of 55 mg of sotalol hydrochloride in 1 hour.

DETAILED DESCRIPTION Definitions

As used in this disclosure, the term “or” is defined as a logicaldisjunction (i.e., and/or) and does not indicate an exclusivedisjunction unless expressly indicated as such with the terms “either,”“unless,” “alternatively,” and words of similar effect.

As used herein, the term “about” means +/−10% of the value specified. Byway of example only, “about 50” means from 45 to 55.

The term “C_(max)” refers to the maximum blood concentration shown onthe curve that represents changes in blood concentrations of an activepharmaceutical ingredient (e.g., sotalol hydrochloride), or a metaboliteof the active pharmaceutical ingredient, over time.

The term “steady state C_(max)” refers to the state, wherein the postdose maximum plasma concentration of sotalol hydrochloride does notdiffer from one dose to another. In some embodiments, the methoddescribed herein provides a steady state C_(max) of sotalolhydrochloride concentration in a range between about 800 ng/mL and about1600 ng/mL, depending upon the amount of sotalol dosed.

The term “QT” refers to a telltale measurement seen on anelectrocardiogram (ECG). The QT interval is measured from the start ofthe Q wave or the QRS complex, to the end of the T wave, where the Qwave corresponds to the beginning of ventricular depolarization and theT wave end corresponds to the end of ventricular repolarization.

The term “QTc” refers to a calculated interval that represents the QTinterval corrected for heart rate. The QTc interval may be derived bysimple mathematical correlation of the QT interval and the heart rate.In preferred embodiments, and for purposes of the present disclosure,the QTc interval is measured using the Bazett formula. Other methods,however, are known in the art, such as the nomogram method, theFrederica formula, or the linear regression equation.

The term “ΔQTc” refers to the difference between a QTc measurement takenprior to intravenous sotalol hydrochloride administration and a QTcmeasured after intravenous sotalol hydrochloride administration.

The term “PO” stands for “per os” and refers to an oral dosing regimen.

The term “BID” stands for “bis in die” and means twice a day.

The term “subject” refers to a human subject.

An “effective amount” of a drug necessary to achieve a therapeuticeffect may vary according to factors such as the age, sex, and weight ofthe subject. Dosage regimens can be adjusted to provide the optimumtherapeutic response.

The terms “treat,” “treating,” and “treatment” refer to any indicia ofsuccess in the treatment or amelioration of an injury, disease, orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,disease, or condition more tolerable to the subject; slowing in the rateof degeneration or decline; or improving a subject's physical or mentalwell-being. The treatment or amelioration of symptoms can be based onobjective or subject parameters, including the results of a physicalexamination, neuropsychiatric examinations, or psychiatric evaluation.

Intravenous sotalol was approved by the FDA in 2009. Although FDAguidance requires a slow infusion over five hours coupled with multi-daycardiac monitoring, it has now been surprisingly discovered that it ispossible to safely reach a sotalol steady state C_(max) in a subjectequal to the sotalol steady state C_(max) typically achieved after BIDPO sotalol administration for three days at various sotalol dosagestrengths, after about 1 hour of intravenous administration. The abilityto reach a steady state C_(max) equal to the steady state C_(max)achieved via oral dosing is surprising because rapid, intravenoussotalol administration was thought to result in high sotalol serumconcentration, excessive QT interval prolongation, and on occasion,Torsade de Pointes ventricular tachycardia. See, Somberg, et. al., Am.J. Ther. 17(4):365-72 (2010).

Sotalol Initiation Protocol in Naïve Subjects

It has been surprisingly discovered that an about 55 mg to about 64 mgintravenous load of sotalol can be safely delivered over about 1 hour toreach a projected steady state C_(max) of about 800 ng/mL (correspondingto the steady state C_(m)ax achieved after three days of PO BID dosingof 80 mg sotalol hydrochloride) in sotalol naive subjects. It haslikewise been surprisingly discovered that an about 82 mg to about 96 mgintravenous load of sotalol hydrochloride delivered over about 1 hourcan safely provide a projected steady state C_(max) of about 1200 ng/mL(corresponding to the steady state C_(max) achieved after three days ofPO BID dosing of 120 mg sotalol hydrochloride) in sotalol naïve subjectsand that an about 110 mg to about 128 mg intravenous load of sotalolhydrochloride delivered over about 1 hour can safely provide a projectedsteady state C_(max) of about 1600 ng/mL (corresponding to the steadystate C_(max) achieved after three days of PO BID dosing of 160 mgsotalol hydrochloride) in naïve subjects. In each of these cases,intravenous administration of sotalol hydrochloride can be followed atappropriate intervals by oral sotalol hydrochloride to maintain thesteady state C_(max) for efficacious treatment or prevention of a givencondition.

By administering sotalol according to the dosing protocol describedherein, a subject can be discharged from the hospital from about 18hours to about 24 hours after initiation of intravenous sotaloladministration. During the 18-24 hour period, the subject typicallyexperiences at least two sotalol concentration peaks: one followingintravenous sotalol hydrochloride administration and one followingsubsequent oral sotalol hydrochloride administration. In someembodiments, the subject experiences two sotalol concentration peaksover a period of about 15 hours to about 18 hours. In each instance, thesubject's peak plasma concentration will approach the steady stateC_(max) observed during chronic dosing. As a result, it is possible toassess the QTc interval of a subject corresponding to the fullconcentration effect of sotalol hydrochloride over an 18-24 hour periodand to determine within that period, if the subject can tolerate thedose.

Accordingly, in some embodiments, this disclosure provides a method ofsafely administering sotalol hydrochloride to a subject in need thereof,the method comprising intravenously administering sotalol hydrochlorideover a period of about 60 minutes to reach a sotalol steady stateC_(max) in the subject, wherein the subject has a QTc interval duringthe intravenous administration of sotalol hydrochloride that is lessthan or equal to 480 msec to 500 msec; and wherein the subject has aΔQTc during sotalol hydrochloride administration that is less than 20%of the subject's QTc prior to intravenous sotalol administration. Insome embodiments, this disclosure provides a method of safelyadministering sotalol hydrochloride to a subject in need thereof, themethod comprising intravenously administering sotalol hydrochloride overa period of about 60 minutes to reach a sotalol steady state C_(max) inthe subject, wherein the subject has a QTc interval during theintravenous administration of sotalol hydrochloride that is less than orequal to 480 msec; and wherein the subject has a ΔQTc during sotalolhydrochloride administration that is less than 20% of the subject's QTcprior to intravenous sotalol administration. In other embodiments, thisdisclosure provides a method of safely administering sotalolhydrochloride to a subject in need thereof, the method comprisingintravenously administering sotalol hydrochloride over a period of about60 minutes to reach a sotalol steady state C_(max) in the subject,wherein the subject has a QTc interval during the intravenousadministration of sotalol hydrochloride that is less than or equal to500 msec; and wherein the subject has a ΔQTc during sotalolhydrochloride administration that is less than 20% of the subject's QTcprior to intravenous sotalol administration.

In some embodiments, about 49.5 to about 70.4 mg of sotalolhydrochloride can be administered intravenously over about 60 minutes toprovide an average sotalol steady state C_(max) of about 800 ng/mL. In aparticular embodiment, about 55 mg to about 64 mg of sotalolhydrochloride can be administered intravenously over about 60 minutes toprovide an average sotalol steady state C_(max) of 800 ng/mL. In someembodiments, about 55 mg to about 64 mg of intravenous sotalolhydrochloride administered over about a 60 minute period can provide asotalol steady state C_(max) of between about 600 ng/mL and about 1000ng/mL, between about 600 ng/mL and about 900 ng/mL, between about 600ng/mL and about 850 ng/mL, between about 600 ng/mL and about 800 ng/mL,between about 600 ng/mL and about 750 ng/mL, between about 600 ng/mL andabout 700 ng/mL, between about 700 ng/mL and about 1000 ng/mL, betweenabout 700 ng/mL and about 900 ng/mL, between about 700 ng/mL and about850 ng/mL, between about 700 ng/mL and about 800 ng/mL, between about700 ng/mL and about 750 ng/mL, between about 750 ng/mL and about 1000ng/mL, between about 750 ng/mL and about 900 ng/mL, between about 750ng/mL and about 850 ng/mL, between about 750 ng/mL and about 800 ng/mL,between about 800 ng/mL and about 1000 ng/mL, between about 800 ng/mLand about 900 ng/mL, between about 800 ng/mL and about 850 ng/mL,between about 850 ng/mL and about 1000 ng/mL, between about 850 ng/mLand about 900 ng/mL, or between about 900 ng/mL and about 1000 ng/mL. Inparticular embodiments, an about 55 mg to about 64 mg intravenous loadof sotalol hydrochloride administered over about 60 minutes can providea steady state C_(max) of between about 750 ng/mL and about 850 ng/mL.

In some embodiments, between about 0.825 mg/min and about 1.17 mg/min ofsotalol hydrochloride can be intravenously administered over the about60 minute period to achieve the desired steady state C_(max).

In another embodiment, about 73.8 to about 105.6 mg of sotalolhydrochloride can be administered intravenously over about 60 minutes toprovide an average sotalol steady state C_(max) of about 1200 ng/mL. Ina particular embodiment, about 82 mg to about 96 mg of sotalolhydrochloride can be administered intravenously over about 60 minutes toprovide an average sotalol steady state C_(max) of about 1200 ng/mL. Insome embodiments, about 82 mg to about 96 mg of intravenous sotalolhydrochloride administered over about 60 minutes can provide a steadystate C_(max) of between about 1000 ng/mL and about 1400 ng/mL, betweenabout 1000 ng/mL and about 1300 ng/mL, between about 1000 ng/mL andabout 1250 ng/mL, between about 1000 ng/mL and about 1200 ng/mL, betweenabout 1000 ng/mL and about 1150 ng/mL, between about 1000 ng/mL andabout 1100 ng/mL, between about 1100 ng/mL and about 1400 ng/mL, betweenabout 1100 ng/mL and about 1300 ng/mL, between about 1100 ng/mL andabout 1250 ng/mL, between about 1100 ng/mL and about 1200 ng/mL, betweenabout 1100 ng/mL and about 1150 ng/mL, between about 1150 ng/mL andabout 1400 ng/mL, between about 1150 ng/mL and about 1300 ng/mL, betweenabout 1150 ng/mL and about 1250 ng/mL, between about 1150 ng/mL andabout 1200 ng/mL, between about 1200 ng/mL and about 1400 ng/mL, betweenabout 1200 ng/mL and about 1300 ng/mL, between about 1200 ng/mL andabout 1250 ng/mL, between about 1250 ng/mL and about 1400 ng/mL, betweenabout 1250 ng/mL and about 1300 ng/mL, or between about 1300 ng/mL andabout 1400 ng/mL. In particular embodiments, about 82 mg to about 96 mgof sotalol hydrochloride administered intravenously over about 60minutes can provide a steady state C_(max) of between about 1150 ng/mLand about 1250 ng/mL.

In some embodiments, an intravenous dose of between about 1.23 mg/minand about 1.76 mg/min of sotalol hydrochloride can be administered overa period of about 60 minutes to achieve the desired steady stateC_(max).

In yet another embodiment, about 99 to 140.8 mg of sotalol hydrochloridecan be administered intravenously over about 60 minutes to provide anaverage sotalol steady state C_(max) of about 1600 ng/mL. In aparticular embodiment, about 110 mg to about 128 mg of sotalolhydrochloride can be administered intravenously over about 60 minutes toprovide an average sotalol steady state C_(max) of about 1600 ng/mL. Insome embodiments, about 110 mg to about 128 mg of intravenous sotalolhydrochloride administered over a period of about 60 minutes can providea steady state C_(max) of between about 1400 ng/mL and about 1800 ng/mL,between about 1400 ng/mL and about 1700 ng/mL, between about 1400 ng/mLand about 1650 ng/mL, between about 1400 ng/mL and about 1600 ng/mL,between about 1400 ng/mL and about 1550 ng/mL, between about 1400 ng/mLand about 1500 ng/mL, between about 1500 ng/mL and about 1800 ng/mL,between about 1500 ng/mL and about 1700 ng/mL, between about 1500 ng/mLand about 1650 ng/mL, between about 1500 ng/mL and about 1600 ng/mL,between about 1500 ng/mL and about 1550 ng/mL, between about 1550 ng/mLand about 1800 ng/mL, between about 1550 ng/mL and about 1700 ng/mL,between about 1550 ng/mL and about 1650 ng/mL, between about 1550 ng/mLand about 1600 ng/mL, between about 1600 ng/mL and about 1800 ng/mL,between about 1600 ng/mL and about 1700 ng/mL, between about 1600 ng/mLand about 1650 ng/mL, between about 1650 ng/mL and about 1800 ng/mL,between about 1650 ng/mL and about 1700 ng/mL, or between about 1700ng/mL and about 1800 ng/mL. In some embodiments, about 110 mg to about128 mg of sotalol hydrochloride administered intravenously over about 60minutes can provide a steady state C_(max) of between about 1550 ng/mLand about 1650 ng/mL.

In some embodiments, between about 1.65 mg/min and about 2.35 mg/min ofsotalol hydrochloride can be intravenously administered over the about60 minute period.

Typically, for each of the embodiments described above, the QTc intervalof a subject is measured 5 to 15 minutes prior to sotalol initiation andsubsequently at 15 minute intervals during intravenous sotaloladministration and for about 90 minutes after intravenous administrationof sotalol hydrochloride is complete. In other embodiments, the QTcinterval of a subject is monitored continuously via telemetry uponintravenous administration of sotalol hydrochloride up to about 90minutes following complete administration of the drug. It is within theskill of an ordinarily skilled cardiologist to calculate ΔQTc based onthese measurements and to increase or decrease sotalol administrationappropriately.

In some embodiments, where a subject has been initiated on about 55 mgto about 64 mg of intravenous sotalol over about a 60 minute period, 80mg of sotalol hydrochloride can be administered orally between about 1hour and about 6 hours after the completion of the intravenousadministration of the about 55 mg to about 64 mg of sotalolhydrochloride. In some embodiments, 80 mg of sotalol hydrochloride canbe administered orally between about 1 hour and about 6 hours, betweenabout 2 hours and about 5 hours, between about 2 hours and about 4hours, between about 2 hours and about 3 hours, between about 3 hoursand about 6 hours, between about 3 hours and about 5 hours, betweenabout 3 hours and about 4 hours, between about 4 hours and about 6hours, between about 4 hours and about 5 hours, or between about 5 hoursand about 6 hours after the completion of the intravenous administrationof about 55 mg to about 64 mg of sotalol hydrochloride.

In some embodiments, between about 2 hours and 5 hours after oraladministration of 80 mg of sotalol hydrochloride, further oraladministration is discontinued or reduced when the subject has a QTcinterval that is greater than 480 msec to 500 msec; or when the subjecthas a ΔQTc that is greater than or equal to 20% of the subject's QTcprior to sotalol administration. In some embodiments, between about 2hours and 5 hours after oral administration of 80 mg of sotalolhydrochloride, further oral administration is discontinued or reducedwhen the subject has a QTc interval that is greater than 480 msec; orwhen the subject has a ΔQTc that is greater than or equal to 20% of thesubject's QTc prior to sotalol administration. In other embodiments,between about 2 hours and 5 hours after oral administration of 80 mg ofsotalol hydrochloride, further oral administration is discontinued orreduced when the subject has a QTc interval that is greater than 500msec; or when the subject has a ΔQTc that is greater than or equal to20% of the subject's QTc prior to sotalol administration.

Alternatively, and in another embodiment, a BID regimen of PO 80 mgsotalol hydrochloride can be initiated when the subject has a QTcinterval at between about 2 hours and about 3 hours after the initialoral administration of sotalol hydrochloride that is less than or equalto 480 msec to 500 msec; or when the subject has a ΔQTc that is lessthan 20% of the subject's QTc prior to sotalol administration. In someembodiments, a BID regimen of PO 80 mg sotalol hydrochloride can beinitiated when the subject has a QTc interval at between about 2 hoursand about 3 hours after the initial oral administration of sotalolhydrochloride that is less than or equal to 480 msec; or when thesubject has a ΔQTc that is less than 20% of the subject's QTc prior tosotalol administration. In other embodiments, a BID regimen of PO 80 mgsotalol hydrochloride can be initiated when the subject has a QTcinterval at between about 2 hours and about 3 hours after the initialoral administration of sotalol hydrochloride that is less than or equalto 500 msec; or when the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to sotalol administration.

In another embodiment, such when the subject exhibits impaired renalfunction, i.e. a glomerular filtration rate (GFR) of between about 45-60mL/min, the maintenance dose of oral sotalol can be administered over alonger dosing interval. For example, a once daily regimen of 80 mg POsotalol hydrochloride can be initiated when the subject has a QTcinterval at between about 2 hours and about 3 hours after initial oraladministration of 80 mg of sotalol hydrochloride that is less than orequal to 500 msec; or when the subject has a ΔQTc that is less than 20%of the subject's QTc prior to sotalol administration.

In some embodiments, where a subject has been initiated on about 82 mgto about 96 mg of intravenous sotalol over about a 60 minute period, 120mg of sotalol hydrochloride can be administered orally between about 1hour and about 6 hours after completion of the intravenousadministration of the about 82 mg to about 96 mg of sotalolhydrochloride. In some embodiments, 120 mg of sotalol hydrochloride isadministered orally between about 2 hours and about 6 hours, betweenabout 2 hours and about 5 hours, between about 2 hours and about 4hours, between about 2 hours and about 3 hours, between about 3 hoursand about 6 hours, between about 3 hours and about 5 hours, betweenabout 3 hours and about 4 hours, between about 4 hours and about 6hours, between about 4 hours and about 5 hours, or between about 5 hoursand about 6 hours after completion of the intravenous administration ofabout 82 mg to about 96 mg of sotalol hydrochloride.

In some embodiments, between about 2 hours and 5 hours after oraladministration of 120 mg of sotalol hydrochloride, further oraladministration is discontinued or reduced when the subject has a QTcinterval that is greater than 480 to 500 msec; or when the subject has aΔQTc that is greater than or equal to 20% of the subject's QTc prior toinitial oral administration of sotalol hydrochloride. In a particularembodiment, between about 2 hours and 5 hours after oral administrationof 120 mg of sotalol hydrochloride, further oral administration isdiscontinued or reduced when the subject has a QTc interval that isgreater than 480 msec; or when the subject has a ΔQTc that is greaterthan or equal to 20% of the subject's QTc prior to initial oraladministration of sotalol hydrochloride. In another embodiment, betweenabout 2 hours and 5 hours after oral administration of 120 mg of sotalolhydrochloride, further oral administration is discontinued or reducedwhen the subject has a QTc interval that is greater than 500 msec; orwhen the subject has a ΔQTc that is greater than or equal to 20% of thesubject's QTc prior to initial oral administration of sotalolhydrochloride.

Alternatively, and in another embodiment, a BID regimen of PO 120 mgsotalol hydrochloride can be initiated when the subject has a QTcinterval at between about 2 hours and about 3 hours after initial oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or when the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to sotalol administration. In a particularembodiment, a BID regimen of PO 120 mg sotalol hydrochloride can beinitiated when the subject has a QTc interval at between about 2 hoursand about 3 hours after initial oral administration of sotalolhydrochloride that is less than or equal to 480 msec; or when thesubject has a ΔQTc that is less than 20% of the subject's QTc prior tosotalol administration. In another embodiment, a BID regimen of PO 120mg sotalol hydrochloride can be initiated when the subject has a QTcinterval at between about 2 hours and about 3 hours after initial oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or when the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to sotalol administration.

In another embodiment, such when the subject exhibits impaired renalfunction, i.e. a glomerular filtration rate (GFR) of between about 45-60mL/min, the maintenance dose of oral sotalol can be administered over alonger dosing interval. For example, a once daily regimen of 120 mg POsotalol hydrochloride can be initiated when the subject has a QTcinterval at between about 2 hours and about 3 hours after initial oraladministration of 120 mg of sotalol hydrochloride that is less than orequal to 500 msec; or when the subject has a ΔQTc that is less than 20%of the subject's QTc prior to sotalol administration.

In some embodiments, where a subject has been initiated on about 110 mgto about 128 mg of intravenous sotalol over about a 60 minute period,160 mg of sotalol hydrochloride can be administered orally between about1 hour and about 6 hours after completion of the intravenousadministration of about 110 mg to about 128 mg of sotalol hydrochloride.In some embodiments, 160 mg of sotalol hydrochloride can be administeredorally between about 2 hours and about 6 hours, between about 2 andabout 5 hours, between about 2 and about 4 hours, between about 2 hoursand about 3 hours, between about 3 hours and about 6 hours, betweenabout 3 hours and about 5 hours, between about 3 hours and about 4hours, between about 4 hours and about 6 hours, between about 4 hoursand about 5 hours, or between about 5 hours and about 6 hours aftercompletion of the intravenous administration of about 110 mg to about128 mg of sotalol hydrochloride.

In some embodiments, between about 2 hours and 5 hours after initialoral administration of 160 mg of sotalol hydrochloride, further oraladministration can be discontinued or reduced when the subject has a QTcinterval that is greater than 480 to 500 msec; or when the subject has aΔQTc that is greater than or equal to 20% of the subject's QTc prior tosotalol administration. In one embodiment, between about 2 hours and 5hours after initial oral administration of 160 mg of sotalolhydrochloride, further oral administration can be discontinued orreduced when the subject has a QTc interval that is greater than 480msec; or when the subject has a ΔQTc that is greater than or equal to20% of the subject's QTc prior to sotalol administration. In anotherembodiment, between about 2 hours and 5 hours after initial oraladministration of 160 mg of sotalol hydrochloride, further oraladministration can be discontinued or reduced when the subject has a QTcinterval that is greater than 500 msec; or when the subject has a ΔQTcthat is greater than or equal to 20% of the subject's QTc prior tosotalol administration.

Alternatively, and in another embodiment, a BID regimen of PO of 160 mgof sotalol hydrochloride can be initiated when the subject has a QTcinterval at between about 2 hours and about 3 hours after initial oraladministration of sotalol hydrochloride that is less than or equal to480 to 500 msec; or when the subject has a ΔQTc that is less than 20% ofthe subject's QTc prior to sotalol administration. In a particularembodiment, a BID regimen of PO of 160 mg of sotalol hydrochloride canbe initiated when the subject has a QTc interval at between about 2hours and about 3 hours after initial oral administration of sotalolhydrochloride that is less than or equal to 480 msec; or when thesubject has a ΔQTc that is less than 20% of the subject's QTc prior tosotalol administration. In another embodiment, a BID regimen of PO of160 mg of sotalol hydrochloride can be initiated when the subject has aQTc interval at between about 2 hours and about 3 hours after initialoral administration of sotalol hydrochloride that is less than or equalto 500 msec; or when the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to sotalol administration.

In another embodiment, such when the subject exhibits impaired renalfunction, i.e. a glomerular filtration rate (GFR) of between about 45-60mL/min, the maintenance dose of oral sotalol can be administered over alonger dosing interval. For example, a once daily regimen of 160 mg POsotalol hydrochloride can be initiated when the subject has a QTcinterval at between about 2 hours and about 3 hours after initial oraladministration of 160 mg of sotalol hydrochloride that is less than orequal to 500 msec; or when the subject has a ΔQTc that is less than 20%of the subject's QTc prior to sotalol administration.

Dose Escalation Protocol

The method of rapid sotalol introduction described herein can also beapplied to dose escalation, for example when a subject needs totransition from 80 mg BID PO to 120 mg BID PO; or from 120 mg BID PO to160 mg BID PO.

For example, subjects receiving 80 or 120 mg BID PO sotalolhydrochloride can be safely transitioned to 120 or 160 mg BID PO sotalolhydrochloride, respectively, via the administration of an intravenousinfusion about 12 hours after the last oral dose of sotalolhydrochloride, i.e. when the concentration of sotalol hydrochloride isat a trough (steady state C_(min)).

Dose Escalation to from 80 mg to 120 mg Oral Sotalol Hydrochloride

In some embodiments, about 49.5 to about 70.4 mg of sotalolhydrochloride can be administered intravenously over about 60 minutes toprovide an average sotalol steady state C_(ma), of about 1200 ng/mL. Ina particular embodiment, about 55 mg to about 64 mg of sotalolhydrochloride can be safely administered intravenously over a period ofabout 60 minutes to provide an average sotalol steady state C_(max) ofabout 1200 ng/mL (corresponding to the steady state C_(max) achievedafter three days of PO BID dosing of 120 mg sotalol hydrochloride) in asubject dosed with 80 mg of oral sotalol hydrochloride between about 12hours and about 24 hours before the intravenous administration. In someembodiments, the sotalol hydrochloride can be administered to thesubject at a rate between about 0.825 mg/min and about 1.17 mg/min overa period of about 60 minutes.

In some embodiments, during administration of between about 0.825 mg/minand about 1.17 mg/min of sotalol hydrochloride over a period of about 60minutes, intravenous administration is discontinued or reduced when thesubject has a QTc interval that is greater than 480 to 500 msec; or whenthe subject has a ΔQTc that is greater than or equal to 20% of thesubject's QTc prior to sotalol administration. In a particularembodiment, during administration of between about 0.825 mg/min andabout 1.17 mg/min of sotalol hydrochloride over a period of about 60minutes, intravenous administration is discontinued or reduced when thesubject has a QTc interval that is greater than 480 msec; or when thesubject has a ΔQTc that is greater than or equal to 20% of the subject'sQTc prior to sotalol administration. In another embodiment, duringadministration of between about 0.825 mg/min and about 1.17 mg/min ofsotalol hydrochloride over a period of about 60 minutes, intravenousadministration is discontinued or reduced when the subject has a QTcinterval that is greater than 500 msec; or when the subject has a ΔQTcthat is greater than or equal to 20% of the subject's QTc prior tosotalol administration.

Alternatively, and in other embodiments, 120 mg of sotalol hydrochloridecan be administered orally between about 1 hour and about 6 hours afterthe completion of the intravenous administration of about 55 mg to about64 mg of sotalol hydrochloride. In some embodiments, 120 mg of sotalolhydrochloride is administered orally between about 1 hour and about 6hours, between about 2 and about 5 hours, between about 2 and about 4hours, between about 2 hours and about 3 hours, between about 3 hoursand about 6 hours, between about 3 hours and about 5 hours, betweenabout 3 hours and about 4 hours, between about 4 hours and about 6hours, between about 4 hours and about 5 hours, or between about 5 hoursand about 6 hours after the completion of the intravenous administrationof about 55 mg to about 64 mg of sotalol hydrochloride.

In some embodiments, oral administration is discontinued or reduced whenthe subject has a QTc interval that is greater than 480 msec to 500msec; or when the subject has a ΔQTc that is greater than or equal to20% of the subject's QTc prior to the oral administration of sotalolhydrochloride. In a particular embodiment, oral administration isdiscontinued or reduced when the subject has a QTc interval that isgreater than 480 msec; or when the subject has a ΔQTc that is greaterthan or equal to 20% of the subject's QTc prior to the oraladministration of sotalol hydrochloride. In another embodiment, oraladministration is discontinued or reduced when the subject has a QTcinterval that is greater than 500 msec; or when the subject has a ΔQTcthat is greater than or equal to 20% of the subject's QTc prior to theoral administration of sotalol hydrochloride.

In other embodiments, BID PO administration of 120 mg of sotalolhydrochloride can be initiated when the subject has a QTc interval atbetween about 2 hours and about 3 hours after oral administration of 120mg of sotalol hydrochloride that is less than or equal to 480 msec to500 msec; or when the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to sotalol administration. In a particularembodiment, BID PO administration of 120 mg of sotalol hydrochloride canbe initiated when the subject has a QTc interval at between about 2hours and about 3 hours after oral administration of 120 mg of sotalolhydrochloride that is less than or equal to 480 msec; or when thesubject has a ΔQTc that is less than 20% of the subject's QTc prior tosotalol administration. In another embodiment, BID PO administration of120 mg of sotalol hydrochloride can be initiated when the subject has aQTc interval at between about 2 hours and about 3 hours after oraladministration of 120 mg of sotalol hydrochloride that is less than orequal to 500 msec; or when the subject has a ΔQTc that is less than 20%of the subject's QTc prior to sotalol administration.

Subjects with impaired renal function safely transitioned to the higherdose can take 120 mg sotalol once daily as discussed elsewhere herein.

Dose Escalation from 120 mg to 160 mg Oral Sotalol Hydrochloride

In some embodiments, about 63 to about 88 mg of sotalol hydrochloridecan be administered intravenously over about 60 minutes to provide anaverage sotalol steady state C_(max) of about 1600 ng/mL. In aparticular embodiment, about 70 mg to about 80 mg of sotalolhydrochloride can be safely administered intravenously over a period ofabout 60 minutes to provide an average sotalol steady state C_(max) ofabout 1600 ng/mL (corresponding to the steady state C_(max) achievedafter three days of PO BID dosing of 160 mg sotalol hydrochloride) in asubject dosed with 120 mg of oral sotalol hydrochloride between about 12hours and about 24 hours before the intravenous administration. In someembodiments, the sotalol hydrochloride can be administered to thesubject at a rate between about 1.05 mg/min and about 1.47 mg/min over aperiod of about 60 minutes.

In some embodiments, during administration of between about 1.05 mg/minand about 1.47 mg/min of sotalol hydrochloride over a period of about 60minutes, intravenous administration is discontinued or reduced when thesubject has a QTc interval that is greater than 480 to 500 msec; or whenthe subject has a ΔQTc that is greater than or equal to 20% of thesubject's QTc prior to sotalol administration. In one embodiment, duringadministration of between about 1.05 mg/min and about 1.47 mg/min ofsotalol hydrochloride over a period of about 60 minutes, intravenousadministration is discontinued or reduced when the subject has a QTcinterval that is greater than 480 msec; or when the subject has a ΔQTcthat is greater than or equal to 20% of the subject's QTc prior tosotalol administration. In another embodiment, during administration ofbetween about 1.05 mg/min and about 1.47 mg/min of sotalol hydrochlorideover a period of about 60 minutes, intravenous administration isdiscontinued or reduced when the subject has a QTc interval that isgreater than 500 msec; or when the subject has a ΔQTc that is greaterthan or equal to 20% of the subject's QTc prior to sotaloladministration.

Alternatively, and in other embodiments, 160 mg of sotalol hydrochloridecan be administered orally between about 1 hour and about 6 hours afterthe completion of the intravenous administration of about 70 mg to about80 mg of sotalol hydrochloride. In some embodiments, 160 mg of sotalolhydrochloride can be administered orally between about 1 hour and about6 hours, between about 2 hours and about 5 hours, between about 2 hoursand about 4 hours, between about 2 hours and about 3 hours, betweenabout 3 hours and about 6 hours, between about 3 hours and about 5hours, between about 3 hours and about 4 hours, between about 4 hoursand about 6 hours, between about 4 hours and about 5 hours, or betweenabout 5 hours and about 6 hours after the completion of the intravenousadministration of about 70 mg to about 80 mg of sotalol hydrochloride.

In some embodiments, further oral administration is discontinued orreduced when the subject has a QTc interval that is greater than 480msec to 500 msec; or when the subject has a ΔQTc that is greater than orequal to 20% of the subject's QTc prior to sotalol administration. Inone embodiment, further oral administration is discontinued or reducedwhen the subject has a QTc interval that is greater than 480 msec; orwhen the subject has a ΔQTc that is greater than or equal to 20% of thesubject's QTc prior to sotalol administration. In another embodiment,further oral administration is discontinued or reduced when the subjecthas a QTc interval that is greater than 500 msec; or when the subjecthas a ΔQTc that is greater than or equal to 20% of the subject's QTcprior to sotalol administration.

In other embodiments, BID PO administration of 160 mg of sotalolhydrochloride can be initiated when the subject has a QTc interval atbetween about 2 hours and about 3 hours after initial oraladministration of sotalol hydrochloride that is less than or equal to480 msec to 500 msec; or when the subject has a ΔQTc that is less than20% of the subject's QTc prior to sotalol administration. In someembodiments, BID PO administration of 160 mg of sotalol hydrochloridecan be initiated when the subject has a QTc interval at between about 2hours and about 3 hours after initial oral administration of sotalolhydrochloride that is less than or equal to 480 msec; or when thesubject has a ΔQTc that is less than 20% of the subject's QTc prior tosotalol administration. In other embodiments, BID PO administration of160 mg of sotalol hydrochloride can be initiated when the subject has aQTc interval at between about 2 hours and about 3 hours after initialoral administration of sotalol hydrochloride that is less than or equalto 500 msec; or when the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to sotalol administration.

Subjects with impaired renal function safely transitioned to the higherdose can take 160 mg sotalol once daily as discussed elsewhere herein.

Method of Reducing Hospital Stay

In some embodiments, the disclosure provides a method of reducing ahospital stay in a subject in need of treatment or prevention of atrialfibrillation, atrial flutter, or a combination thereof, the methodcomprising introducing a subject to sotalol hydrochloride administeredintravenously over a period of about 60 minutes in the absence offurther sotalol administration for a period of about 1 hour to about 6hours after the period of about 60 minutes.

In some embodiments, about 0.825 mg/min to about 1.17 mg/min of sotalolhydrochloride is intravenously administered over the about 60 minuteperiod. In some embodiments, the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about750 ng/mL and about 850 ng/mL in the subject.

In some embodiments, about 1.23 mg/min to about 1.76 mg/min of sotalolhydrochloride is intravenously administered over the about 60 minuteperiod. In some embodiments, the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about1150 ng/mL and about 1250 ng/mL in the subject.

In some embodiments, about 1.65 mg/min to about 2.35 mg/min of sotalolhydrochloride is intravenously administered over the about 60 minuteperiod. In some embodiments, the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about1550 ng/mL and about 1650 ng/mL in the subject.

In some embodiments, where the subject received 80 mg oral sotalolhydrochloride about 12 hours to about 24 hours before the intravenousadministration, about 0.825 mg/min to about 1.17 mg/min of sotalolhydrochloride can be intravenously administered over the about 60 minuteperiod to safely escalate sotalol hydrochloride dosing to 120 mg oralsotalol hydrochloride.

In yet another embodiment, where the subject received 120 mg oralsotalol hydrochloride about 12 hours to about 24 hours before theintravenous administration, between about 1.05 mg/min and about 1.47mg/min of sotalol hydrochloride can be intravenously administered overthe about 60 minute period to safely escalate sotalol hydrochloridedosing to 160 mg oral sotalol hydrochloride.

In any of the embodiments described above, the intravenousadministration of sotalol hydrochloride can be discontinued or reducedwhen the subject has a QTc interval after intravenous sotalolhydrochloride initiation that is greater than 480 msec to 500 msec; orwherein the subject has a ΔQTc that is greater than or equal to 20% ofthe subject's QTc prior to sotalol administration. In any of theembodiments described above, the intravenous administration of sotalolhydrochloride can be discontinued or reduced when the subject has a QTcinterval after intravenous sotalol hydrochloride initiation that isgreater than 480 msec; or wherein the subject has a ΔQTc that is greaterthan or equal to 20% of the subject's QTc prior to sotaloladministration. Alternatively, in any of the embodiments describedabove, the intravenous administration of sotalol hydrochloride can bediscontinued or reduced when the subject has a QTc interval afterintravenous sotalol hydrochloride initiation that is greater than 500msec; or wherein the subject has a ΔQTc that is greater than or equal to20% of the subject's QTc prior to sotalol administration.

In some embodiments, sotalol hydrochloride is orally administeredbetween about 1 hour and about 6 hours after completion of theintravenous administration.

In some embodiments, 80 mg of sotalol hydrochloride can be orallyadministered between about 1 and about 6 hours after completingintravenous administration of about 0.825 mg/min to about 1.17 mg/min ofsotalol hydrochloride.

In some embodiments, 120 mg of sotalol hydrochloride can be orallyadministered between about 1 hour and about 6 hours after completingintravenous administration of about 1.23 mg/min to about 1.76 mg/min ofsotalol hydrochloride.

In some embodiments, 160 mg of sotalol hydrochloride can be orallyadministered between about 1 hour and about 6 hours after completingintravenous administration of about 1.65 mg/min to about 2.35 mg/min ofsotalol hydrochloride.

In some embodiments, the oral administration of sotalol hydrochloride isdiscontinued or reduced when the subject has a QTc interval at betweenabout 2 hours and about 3 hours after oral administration of sotalolhydrochloride that is greater than 500 msec; or wherein the subject hasa ΔQTc that is greater than or equal to 20% of the subject's QTc priorto intravenous sotalol administration. In a particular embodiment, theoral administration of sotalol hydrochloride is discontinued or reducedwhen the subject has a QTc interval at between about 2 hours and about 3hours after oral administration of sotalol hydrochloride that is greaterthan 480 msec; or wherein the subject has a ΔQTc that is greater than orequal to 20% of the subject's QTc prior to intravenous sotaloladministration. In another particular embodiment, the oraladministration of sotalol hydrochloride is discontinued or reduced whenthe subject has a QTc interval at between about 2 hours and about 3hours after oral administration of sotalol hydrochloride that is greaterthan 500 msec; or wherein the subject has a ΔQTc that is greater than orequal to 20% of the subject's QTc prior to intravenous sotaloladministration.

As described elsewhere herein, when a subject has a QTc interval that isacceptable and/or wherein the subject has a ΔQTc that is less than orequal to 20% of the subject's QTc prior to intravenous sotaloladministration, the subject can be transitioned to BID PO dosing, or QD(once daily) PO dosing, as appropriate for the subject's renal function.

EMBODIMENTS

In addition to the various embodiments described above, the presentdisclosure includes the following specific embodiments numbered E1through E27. This list of embodiments is presented as an exemplary listand the application is not limited to these embodiments.

E1. A method of treating or preventing atrial fibrillation, atrialflutter, or a combination thereof in a subject in need thereof, themethod comprising intravenously administering to the subject betweenabout 0.825 mg/min and about 1.17 mg/min of sotalol hydrochloride over aperiod of about 60 minutes.

E2. The method of E1, further comprising discontinuing or reducingintravenous administration of sotalol hydrochloride when the subject hasa QTc interval after intravenous sotalol hydrochloride initiation thatis greater than 500 msec; or wherein the subject has a ΔQTc that isgreater than or equal to 20% of the subject's QTc prior to sotaloladministration.

E3. The method of E1, wherein the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about750 ng/mL and about 850 ng/mL in the subject.

E4. The method of E3, further comprising orally administering to thesubject 80 mg of sotalol hydrochloride between about 1 hour and about 6hours after completion of the intravenous administration.

E5. The method of E4, further comprising discontinuing or reducing oraladministration of sotalol hydrochloride when the subject has a QTcinterval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

E6. The method of E4, further comprising initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and about 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to intravenous sotalol administration.

E7. A method of treating or preventing atrial fibrillation, atrialflutter, or a combination thereof in a subject in need thereof, themethod comprising intravenously administering to the subject betweenabout 1.23 mg/min and about 1.76 mg/min of sotalol hydrochloride over aperiod of about 60 minutes.

E8. The method of E7, further comprising discontinuing or reducingintravenous administration of sotalol hydrochloride when the subject hasa QTc interval after intravenous sotalol hydrochloride initiation thatis greater than 500 msec; or wherein the subject has a ΔQTc that isgreater than or equal to 20% of the subject's QTc prior to sotaloladministration.

E9. The method of E7, wherein the intravenous administration of sotalolhydrochloride results in a sotalol steady state C_(max) of between about1150 ng/mL and about 1250 ng/mL in the subject.

E10. The method of E9, further comprising orally administering to thesubject 120 mg of sotalol hydrochloride between about 1 hour and about 6hours after completion of the intravenous administration.

E11. The method of E10, further comprising discontinuing or reducingoral administration of sotalol hydrochloride when the subject has a QTcinterval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

E12. The method of E10, further comprising initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and about 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% of thesubject's QTc prior to intravenous sotalol administration.

E13. A method of treating atrial fibrillation, atrial flutter, or acombination thereof in a subject in need thereof, the method comprisingintravenously administering to the subject between about 1.65 mg/min andabout 2.35 mg/min of sotalol hydrochloride over a period of about 60minutes.

E14. The method of E13, further comprising discontinuing or reducingintravenous administration of sotalol hydrochloride when the subject hasa QTc interval after intravenous sotalol hydrochloride initiation thatis greater than 500 msec; or wherein the subject has a ΔQTc that isgreater than or equal to 20% of the subject's QTc prior to sotaloladministration.

E15. The method of E13, wherein the intravenous administration ofsotalol hydrochloride results in a sotalol steady state C_(max) ofbetween about 1550 ng/mL and about 1650 ng/mL in the subject.

E16. The method of E15, further comprising orally administering to thesubject 160 mg of sotalol hydrochloride between about 1 hour and about 6hours after completion of the intravenous administration.

E17. The method of E16, further comprising discontinuing or reducingoral administration of sotalol hydrochloride when the subject has a QTcinterval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

E18. The method of E16, further comprising initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% thesubject's QTc prior to intravenous sotalol administration.

E19. A method of treating or preventing atrial fibrillation, atrialflutter, or a combination thereof in a subject in need thereof, themethod comprising intravenously administering to the subject betweenabout 0.825 mg/min and about 1.17 mg/min of sotalol hydrochloride over aperiod of about 60 minutes, wherein the subject received anadministration of sotalol hydrochloride between about 12 hours and about24 hours before the intravenous administration.

E20. The method of E19, wherein the subject received an oraladministration of 80 mg of oral sotalol hydrochloride between about 12and about 24 hours before the intravenous administration.

E21. The method of E19, further comprising discontinuing or reducingintravenous administration of sotalol hydrochloride when the subject hasa QTc interval after intravenous sotalol hydrochloride initiation thatis greater than 500 msec; or wherein the subject has a ΔQTc that isgreater than or equal to 20% of the subject's QTc prior to sotaloladministration.

E22. The method of E19, wherein the intravenous administration ofsotalol hydrochloride results in a sotalol steady state C_(max) ofbetween about 1150 ng/mL and about 1250 ng/mL in the subject.

E23. The method of E22, further comprising orally administering to thesubject 120 mg of sotalol hydrochloride between about 1 hour and about 6hours after completion of the intravenous administration.

E24. The method of E23, further comprising discontinuing or reducingoral administration of sotalol hydrochloride when the subject has a QTcinterval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

E25. The method of E23, further comprising initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% thesubject's QTc prior to intravenous sotalol administration.

E26. A method of treating or preventing atrial fibrillation, atrialflutter, or a combination thereof in a subject in need thereof, themethod comprising intravenously administering to the subject betweenabout 1.05 mg/min and about 1.47 mg/min of sotalol hydrochloride over aperiod of about 60 minutes, wherein the subject received anadministration of sotalol hydrochloride between about 12 hours and about24 hours before the intravenous administration.

E27. The method of E26, wherein the subject received an oraladministration of 120 mg of oral sotalol hydrochloride between about 12and about 24 hours before the intravenous administration.

E28. The method of E26, further comprising discontinuing or reducingintravenous administration of sotalol hydrochloride when the subject hasa QTc interval after intravenous sotalol hydrochloride initiation thatis greater than 500 msec; or wherein the subject has a ΔQTc that isgreater than or equal to 20% of the subject's QTc prior to sotaloladministration.

E29. The method of E26, wherein the intravenous administration ofsotalol hydrochloride results in a sotalol steady state C_(max) ofbetween about 1550 ng/mL and about 1650 ng/mL in the subject.

E30. The method of E29, further comprising orally administering to thesubject 160 mg of sotalol hydrochloride between about 1 hour and about 6hours after completion of the intravenous administration.

E31. The method of E30, further comprising discontinuing or reducingoral administration of sotalol hydrochloride when the subject has a QTcinterval at between about 2 hours and about 5 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

E32. The method of E30, further comprising initiating an oral BIDadministration regimen of sotalol hydrochloride when the subject has aQTc interval at between about 2 hours and 3 hours after oraladministration of sotalol hydrochloride that is less than or equal to500 msec; or wherein the subject has a ΔQTc that is less than 20% thesubject's QTc prior to intravenous sotalol administration.

E33. A method of reducing a hospital stay of a subject in need oftreatment or prevention of atrial fibrillation, atrial flutter, or acombination thereof, the method comprising stabilizing a subject onsotalol hydrochloride administered intravenously over a period of about60 minutes in the absence of further sotalol administration for a periodof about 1 hour to about 6 hours after the period of about 60 minutes.

E34. The method of E33, wherein the hospital stay is reduced to betweenabout 18 hours and about 24 hours.

E35. The method of E33, wherein the hospital stay is reduced to betweenabout 20 hours and about 24 hours.

E36. The method of E33, wherein between about 0.825 mg/min and about1.17 mg/min of sotalol hydrochloride is intravenously administered overthe about 60 minute period.

E37. The method of E33, wherein between about 1.23 mg/min and about 1.76mg/min of sotalol hydrochloride is intravenously administered over theabout 60 minute period.

E38. The method of E33, wherein between about 1.65 mg/min and about 2.35mg/min of sotalol hydrochloride is intravenously administered over theabout 60 minute period.

E39. The method of E33, wherein the subject received oral sotalolhydrochloride between about 12 hours and about 24 hours before theintravenous administration.

E40. The method of E39, wherein between about 0.825 mg/min about 1.17mg/min of sotalol hydrochloride is intravenously administered over theabout 60 minute period.

E41. The method of E39, wherein between about 1.05 mg/min and about 1.47mg/min of sotalol hydrochloride is intravenously administered over theabout 60 minute period.

E42. The method of E33, wherein the intravenous administration ofsotalol hydrochloride is discontinued or reduced when the subject has aQTc interval after intravenous sotalol hydrochloride initiation that isgreater than 500 msec; or wherein the subject has a ΔQTc that is greaterthan or equal to 20% of the subject's QTc prior to sotaloladministration.

E43. The method of E36, wherein the intravenous administration ofsotalol hydrochloride results in a sotalol steady state C_(max) ofbetween about 750 ng/mL and about 850 ng/mL in the subject.

E44. The method of E37, wherein the intravenous administration ofsotalol hydrochloride results in a sotalol steady state C_(max) ofbetween about 1150 ng/mL and about 1250 ng/mL in the subject.

E45. The method of E38, wherein the intravenous administration ofsotalol hydrochloride results in a sotalol steady state C_(max) ofbetween about 1550 ng/mL and about 1650 ng/mL in the subject.

E46. The method E33, further comprising orally administering to thesubject sotalol hydrochloride between about 1 hour and about 6 hoursafter completion of the intravenous administration.

E47. The method of E33, wherein 80 mg of sotalol hydrochloride is orallyadministered between about 5 and about 8 hours after completion ofintravenous administration of between about 0.825 mg/min and about 1.17mg/min of sotalol hydrochloride.

E48. The method of E33, wherein 120 mg of sotalol hydrochloride isorally administered between about 1 hour and about 6 hours aftercompletion of intravenous administration of between about 1.23 mg/minand about 1.76 mg/min of sotalol hydrochloride.

E49. The method of E33, wherein 160 mg of sotalol hydrochloride isorally administered between about 1 hour and about 6 hours aftercompletion of intravenous administration of between about 1.65 mg/minand about 2.35 mg/min of sotalol hydrochloride.

E50. The method of E46, wherein the oral administration of sotalolhydrochloride is discontinued or reduced when the subject has a QTcinterval at between about 2 hours and about 3 hours after oraladministration of sotalol hydrochloride that is greater than 500 msec;or wherein the subject has a ΔQTc that is greater than or equal to 20%of the subject's QTc prior to intravenous sotalol administration.

E51. The method of E46, wherein an oral administration BID regimen ofsotalol hydrochloride is initiated when the subject has a QTc intervalat between about 2 hours and about 3 hours after oral administration ofsotalol hydrochloride that is less than or equal to 500 msec; or whereinthe subject has a ΔQTc that is less than 20% of the subject's QTc priorto intravenous sotalol administration.

E52. A method of administering sotalol hydrochloride to a subject inneed thereof, the method comprising intravenously administering sotalolhydrochloride over a period of about 60 minutes to reach a sotalolsteady state C_(max) in the subject, wherein the subject has a QTcinterval during the intravenous administration of sotalol hydrochloridethat is less than or equal to 500 msec; and wherein the subject has aΔQTc during sotalol hydrochloride administration that is less than 20%of the subject's QTc prior to intravenous sotalol administration.

E53. The method of E52, wherein the sotalol steady state C_(max) isbetween about 750 ng/mL and about 850 ng/mL.

E54. The method of E52, wherein the steady sotalol state C_(max) isbetween about 1150 ng/mL and about 1250 ng/mL.

E55. The method of E52, wherein the steady sotalol state C_(max) isbetween about 1550 ng/mL and about 1650 ng/mL.

E56. The method of E52, wherein between about 0.825 mg/min and about1.17 mg/min of sotalol hydrochloride is intravenously administered overthe about 60 minute period.

E57. The method of E52, wherein between about 1.23 mg/min and about 1.76mg/min of sotalol hydrochloride is intravenously administered over theabout 60 minute period.

E58. The method of E52, wherein between about 1.65 mg/min and about 2.35mg/min of sotalol hydrochloride is intravenously administered over theabout 60 minute period.

E59. A method to administer a loading dose of Sotalol entirelyintravenously to a target maximum serum concentration that a subject isexpected to be exposed in the course of chronic oral dosing of Sotalol.

E60. A method to administer sotalol intravenously to a targetconcentration in order to see the maximum QTc interval increment thatcan be expected to be expressed by a subject in the course of chronicoral therapy, while maximizing subject safety during initial loadingprocess.

E61. A method permitting the targeting of the projected maximumconcentration of sotalol hydrochloride that may be attained on chronicdosing in a period of one hour, permitting the adjustment of the dosing,or its cessation for subject safety dependent on QTc intervalprolongation.

E62. A way to initiate sotalol hydrochloride therapy in a subject withan indication to receive chronic sotalol therapy employing anintravenous infusion.

E63. The use of an intravenous infusion to obtain sotalol hydrochloridesteady state C_(max) concentration to the level obtained with chronicoral sotalol hydrochloride dosing.

E64. A way to obtain steady state C_(max) to observe changes in cardiacrepolarization such that the increase in QTc is not greater thanspecified in guidelines and thus, not risking the development of lifethreatening ventricular arrhythmias.

E65. A method of administering sotalol hydrochloride, observing thechanges in QTc such that if the QTc increases beyond acceptableparameters, the infusion can be terminated immediately, enhancingsubject safety.

E66. A method of increasing sotalol hydrochloride dose from low doseoral therapy to higher dose oral therapy using an intravenous infusion.

E67. A method of dose escalation of sotalol hydrochloride such that theinfusion obtains the projected steady state C_(max) and thus maximum QTcchanges in a brief period of time, avoiding changes in QTc in excess ofthose expected to be experienced by a subject receiving an appropriatedose of sotalol and thus reducing the risk of drug induced arrhythmias.

E68. A method of dose initiation and dose escalation employingintravenous sotalol hydrochloride in subjects with renal dysfunction.Providing the attainment of steady state C_(max) and thus, the fullexposure of QTc changes under electrocardiographic observation within 24hours of exposure.

Examples

The following examples are illustrative and non-limiting, of the methodsdescribed herein. Suitable modifications and adaptations of the varietyof conditions, formulations, and other parameters normally encounteredin the field and which are obvious to those skilled in the art in viewof this disclosure are within the spirit and scope of the invention.

Example 1: IV Sotalol

A subject with a QTc interval of 405 msec is to receive 80 mg of oralsotalol hydrochloride by mouth twice a day (PO BID) with a steady stateserum concentration reached in 3-5 days with a steady state C_(max) of800 ng/mL. With the relationship of QTc to serum concentration onaverage of 0.024:

$\begin{matrix}{{{QTc}\mspace{14mu} \max} = {{{QTc}\mspace{14mu} {baseline}} + \left( {0.024 \times 800\mspace{14mu} {ng}\text{/}{mL}} \right)}} \\{= {424\mspace{14mu} {msec}^{*}}}\end{matrix}$

Dose Initiation: To attenuate the time required to achieve steady stateC_(max), one can administer sotalol hydrochloride IV as an infusion. Forexample, 55 mg (projected to equate to 80 mg by mouth twice a day) of IVsotalol hydrochloride can be administered over 1-2 hours, the steadystate C_(max) estimated for an average person's serum sotalolconcentration 800 ng/mL would be achieved, which would transpose to aQTc prolongation of an average of 427 msec. *Within the prescribed FDAguideline of remaining under a maximum QTc of 500 msec.

Example 2: IV Sotalol

A subject with an initial QTc of 405 msec (average for a 70 kg person)starts receiving a sotalol hydrochloride IV infusion of 55 mg/mL andafter 45 minutes the QTc is measured to be 456 msec. The infusion can behalted and the dose of sotalol hydrochloride selected for chronicadministration can be reduced, the dosing interval can be prolonged, orthe physician can decide not to use sotalol hydrochloride and insteadturn to an alternative anti-arrhythmic therapy.

IV loading could safely expose the subject to the expected maximumsotalol hydrochloride concentration and thus maximum QTc prolongationthat would be expected to occur with chronic dosing. If underobservation, the QTc prolongs to a significantly greater degree, theinfusion can be stopped, the dose reduced, or the subject deemed toosensitive to sotalol hydrochloride dosing and another antiarrhythmicdrug could be evaluated for efficacy and safety in that particularsubject. This approach would be a major safety factor for subjects,since with oral loading or oral and IV loading, the absorption continuesonce a pill is taken and the overshoot in QTc will continue, placing thesubject at greater risk. An infusion thus provides greater safety, sincethe infusion can be stopped with no further significant increase in QTc.

Example 3: IV Sotalol

A 70 kg subject presents with intermittent atrial fibrillation (AF). Hisphysician wants to place the subject on oral sotalol hydrochloride 80 mgPO BID. He has never taken sotalol before. He is admitted to thehospital and receives an infusion of IV sotalol hydrochloride (55 mg)over 1 hour. This infusion achieves a target serum concentration of 800ng/mL. Following the infusion the QTc is checked 30 minutes afteradministration. If the QTc is within guidelines (less than 20% increase,or under 500 msec) an interval of 2-6 hours is left to elapse to reachthe predicted trough and then 80 mg orally is given to subject, whichwill predictably peak in 2-4 hours and QTc will be measured again hourly(at 4-5 hours). If QTc is within guidelines, then dosing will continueorally, 80 mg every 12 hours.

The subject will thus have been exposed to a serum sotalol hydrochlorideconcentration predicted to be reached with chronic dosing (predictedC_(max)) twice in the 16 hours of observation and can be dischargedsafely in 24 hours knowing that the QTc will not at maximum predictedconcentration exceed guidelines. Thus, in a timeframe of between 6-23hours, sotalol hydrochloride could be fully evaluated for repolarizationsafety with the maximum QTc expected at a given chronic dose.

That some subjects respond unpredictably to sotalol hydrochloride, orother QT prolonging drugs is well-known. This can be explained in thecase of sotalol hydrochloride by an abnormality in the potassiumchannel. Genetic conditions can cause mild abnormalities in proteinstructure of the potassium channel. These abnormalities can be dormantand only seen as marked QT prolongation when subjects are exposed to apotassium channel blocker such as sotalol hydrochloride. In thesesubjects with a channelopathy, the QTc may markedly increase withensuing life threatening ventricular arrhythmias and possibly suddencardiac death. Having a way to rapidly access the QTc effect of sotalolhydrochloride by administering an intravenous infusion when the drugadministration could be halted at any time will greatly enhance subjectsafety. As can be seen in FIG. 1, the exposure to sotalol through an IVinfusion over several hours can achieve steady state C_(max) and themaximum QTc in a short period of time (less than 24 hours). Thus,permitting evaluation in hospital over 24 hours as opposed to the 3 dayhospitalization currently needed to achieve steady state C_(max) levelswith oral sotalol hydrochloride dosing.

Another critical factor in the dosing of sotalol hydrochloride toobserve maximum QTc effect is the relation of the serum concentrationand QTc prolongation based on time. The phenomenon is called hysteresis:the delay between a change in a marker affected by an exposure to anagent causing its change. This can be due to delay of the drug reachingthe receptor or channel or changes in the receptor or channel neededover time to be fully expressed. Information on sotalol concentrationand QTc prolongation is known from the work of Somberg and colleagues.In Somberg, J. C., et al., Am J. Ther. 17(4):365-72 (2010). 15 normalindividuals received sotalol hydrochloride infused intravenously andthen at a later date administered orally. The infusion was over a 2.5hour duration and thus the serum concentration would be at a maximum atthe end of infusion (2.5 hours). The maximum QTc was seen at 2.25 hours.Thirty minutes later at hour 3, the QTc had decreased. Thus, thehysteresis between sotalol hydrochloride concentration and QTc cannot belonger than 30 minutes. Therefore, a period of 30 minutes is recommendedto observe the maximum QTc effect after the completion of the infusion,to observe and then act upon the maximum QTc observed.

Dose Escalation

In an analogous manner a subject on a maintenance dose of 80 mg PO BIDsotalol hydrochloride, or 120 mg PO BID could be increased to the nextstandard increment in oral dosing. A subject could be brought in to thehospital at the time before the next dosing interval, nadir of serumconcentration, and administered an infusion over 1-2 hours of IV sotalolhydrochloride to attain the projected next highest concentration level(steady state C_(max)) and thus the maximum concentration the subjectwould be exposed to, resulting in the maximum QTc predicted exposure.This could be done in hospital in less than 24 hours such that the fullrisk to the subject of that serum sotalol hydrochloride concentrationcould be observed as shown in FIG. 2. If arrhythmias occur, cardiacresuscitation measures could be initiated, offering the subject maximalsafety. If the infusion is given intravenously, the infusion could beterminated if the QTc increases beyond acceptable parameters recommendedby FDA in the sotalol hydrochloride product label.

Example 4: IV Sotalol

A subject on 80 mg PO BID is brought to hospital at end of dosinginterval before the next oral dose and then, receives an IV infusion ofsotalol hydrochloride. Trough concentration of sotalol hydrochloridegiven at 80 mg PO BID can be estimated to be 400 ng/mL. The steady stateC_(max) of a 120 mg PO BID dose would be 1200 ng/mL. Thus, an infusionof 55 mg sotalol hydrochloride would achieve a target concentration ofapproximately 1200 ng/mL, exposing the subject to the maximal predictedQTc prolongation in 2 hours or less. In both the initiating and loadingperiods one may then proceed to continue oral dosing after a presetinterval (2-6 hours) to continue sotalol hydrochloride exposure toprovide anti-arrhythmic action during the transition from IV to oraldrug administration.

While the methods have been described in terms of what are presentlyconsidered to be practical and preferred embodiments, it is to beunderstood that the disclosure need not be limited to the disclosedembodiments. It is intended to cover various modifications and similararrangements included within the spirit and scope of the claims, thescope of which should be accorded the broadest interpretation so as toencompass all such modifications and similar embodiments. Thisdisclosure includes any and all embodiments of the following claims.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents, patent applications, and publicationscited herein are fully incorporated by reference herein in theirentirety.

What is claimed:
 1. A method of rapidly initiating or escalating oralsotalol therapy, the method comprising: (1) intravenously (IV)administering over a period of 1 hour, to a subject in need thereof, adosage selected from: (a) about 49.5-70.4 mg of sotalol hydrochloride,wherein the subject: i. was naïve to sotalol; or ii. had received 80 mgof oral sotalol hydrochloride about 12 hours prior to the IVadministration; (b) about 73.8-105.6 mg of sotalol hydrochloride,wherein the subject: i. was naïve to sotalol; or ii. had received 120 mgof oral sotalol hydrochloride about 12 hours prior to the IVadministration; and, (c) about 99-140.8 mg of sotalol hydrochloride to asubject who is naïve to sotalol; and, (2) orally administering every 12hours a dosage selected from: (a) 80 mg of sotalol hydrochloride,starting about 1-6 hours after the completion of the (1)(a)(i) IV dose;(b) 120 mg of sotalol hydrochloride, starting about 1-6 hours after thecompletion of the (1)(b)(i) IV dose; (c) 120 mg of sotalolhydrochloride, starting about 1-6 hours after the completion of the(1)(a)(ii) IV dose; (d) 160 mg of sotalol hydrochloride, starting about1-6 hours after the completion of the (1)(c) IV dose; and, (e) 160 mg ofsotalol hydrochloride, starting about 1-6 hours after the completion ofthe (1)(b)(ii) IV dose; wherein, the subject: A. is sotalol naïve orcurrently on oral sotalol; B. is indicated for chronic but not acutesotalol therapy; C. is under hospitalized QTc monitoring; and, D.experiences 3 sotalol steady state C_(max) in less than 24 hours, whichallows for a QTc interval of the subject that corresponds to the fullconcentration effect of sotalol to be assessed in less than 24 hours. 2.The method of claim 1, wherein the method, comprises: (1) IVadministering over a period of 1 hour, to a subject in need thereof, adosage selected from: (a) about 55-64 mg of sotalol hydrochloride,wherein the subject: i. was naïve to sotalol; or ii. had received 80 mgof oral sotalol hydrochloride about 12 hours prior to the IVadministration; (b) about 82-96 mg of sotalol hydrochloride, wherein thesubject: i. was naïve to sotalol; or ii. had received 120 mg of oralsotalol hydrochloride about 12 hours prior to the IV administration;and, (c) about 110-128 mg of sotalol hydrochloride to a subject who isnaïve to sotalol; and, (2) orally administering every 12 hours a dosageselected from: (a) 80 mg of sotalol hydrochloride, starting about 1 hourafter the completion of the (1)(a)(i) IV dose; (b) 120 mg of sotalolhydrochloride, starting about 1 hour after the completion of the(1)(b)(i) IV dose; (c) 120 mg of sotalol hydrochloride, starting about 4hours after the completion of the (1)(a)(ii) IV dose; (d) 160 mg ofsotalol hydrochloride, starting about 1 hour after the completion of the(1)(c) IV dose; and, (e) 160 mg of sotalol hydrochloride, starting about4 hours after the completion of the (1)(b)(ii) IV dose.
 3. The method ofclaim 1, wherein the method, comprises: (1) IV administering over aperiod of 1 hour, to a subject in need thereof, a dosage selected from:(a) about 64 mg of sotalol hydrochloride, wherein the subject: i. wasnaïve to sotalol; or ii. had received 80 mg of oral sotalolhydrochloride about 12 hours prior to the IV administration; (b) about96 mg of sotalol hydrochloride, wherein the subject: i. was naïve tosotalol; or ii. had received 120 mg of oral sotalol hydrochloride about12 hours prior to the IV administration; and, (c) about 128 mg ofsotalol hydrochloride to a subject who is naïve to sotalol; and, (2)orally administering every 12 hours a dosage selected from: (a) 80 mg ofsotalol hydrochloride, starting about 1 hour after the completion of the(1)(a)(i) IV dose; (b) 120 mg of sotalol hydrochloride, starting about 1hour after the completion of the (1)(b)(i) IV dose; (c) 120 mg ofsotalol hydrochloride, starting about 4 hours after the completion ofthe (1)(a)(ii) IV dose; (d) 160 mg of sotalol hydrochloride, startingabout 1 hour after the completion of the (1)(c) IV dose; and, (e) 160 mgof sotalol hydrochloride, starting about 4 hours after the completion ofthe (1)(b)(ii) IV dose.
 4. The method of claim 1, wherein the method,comprises: (1) IV administering over a period of 1 hour, to a subject inneed thereof and naïve to sotalol, a dosage selected from: (a) about55-64 mg of sotalol hydrochloride; (b) about 82-96 mg of sotalolhydrochloride; and, (c) about 110-128 mg of sotalol hydrochloride; and,(2) orally administering every 12 hours a dosage selected from: (a) 80mg of sotalol hydrochloride, starting about 1 hour after the completionof the (1)(a) IV dose; (b) 120 mg of sotalol hydrochloride, startingabout 1 hour after the completion of the (1)(b) IV dose; and, (c) 160 mgof sotalol hydrochloride, starting about 1 hour after the completion ofthe (1)(c) IV dose.
 5. The method of claim 1, wherein the method,comprises: (1) IV administering over a period of 1 hour, to a subject inneed thereof and naïve to sotalol, a dosage selected from: (a) about 64mg of sotalol hydrochloride; (b) about 96 mg of sotalol hydrochloride;and, (c) about 128 mg of sotalol hydrochloride; and, (2) orallyadministering every 12 hours a dosage selected from: (a) 80 mg ofsotalol hydrochloride, starting about 1 hour after the completion of the(1)(a) IV dose; (b) 120 mg of sotalol hydrochloride, starting about 1hour after the completion of the (1)(b) IV dose; and, (c) 160 mg ofsotalol hydrochloride, starting about 1 hour after the completion of the(1)(c) IV dose.
 6. The method of claim 1, wherein the method, comprises:(1) IV administering over a period of 1 hour, to a subject in needthereof, a dosage selected from: (a) about 55-64 mg of sotalolhydrochloride, wherein the subject had received 80 mg of oral sotalolhydrochloride about 12 hours prior to the IV administration; and, (b)about 82-96 mg of sotalol hydrochloride, wherein the subject hadreceived 120 mg of oral sotalol hydrochloride about 12 hours prior tothe IV administration; and, (2) orally administering every 12 hours adosage selected from: (a) 120 mg of sotalol hydrochloride, startingabout 4 hours after the completion of the (1)(a) IV dose; and, (b) 160mg of sotalol hydrochloride, starting about 4 hours after the completionof the (1)(b) IV dose.
 7. The method of claim 1, wherein the method,comprises: (1) IV administering over a period of 1 hour, to a subject inneed thereof, a dosage selected from: (a) about 70.4 mg of sotalolhydrochloride, wherein the subject had received 80 mg of oral sotalolhydrochloride about 12 hours prior to the IV administration; and, (b)about 96 mg of sotalol hydrochloride, wherein the subject had received120 mg of oral sotalol hydrochloride about 12 hours prior to the IVadministration; and, (2) orally administering every 12 hours a dosageselected from: (a) 120 mg of sotalol hydrochloride, starting about 4hours after the completion of the (1)(a) IV dose; and, (b) 160 mg ofsotalol hydrochloride, starting about 4 hours after the completion ofthe (1)(b) IV dose.